PROJECT SUMMARY/ABSTRACT Seizures are a devastating and often fatal neurological condition that manifests as a standalone disease or as a comorbidity in other debilitating conditions. Unfortunately, treatments are often ineffective, in part because the neural origins of seizures are unclear. As a first step towards identifying seizure loci in the brain, I designed an optogenetic approach in mice that provides a versatile method for generating severe seizures. This approach allows me to test whether specific brain regions have the capacity to initiate seizures and interrogate the circuit mechanisms underlying seizure propagation and maintenance. The seizure model I generated is based on controlling the function of neural circuits in a brain region called the cerebellum, now considered the hub for all motor functions and a central target in a growing list of brain diseases. There is an extensive literature implicating cerebellar dysfunction in epilepsy: in particular, its output may drive the uncontrollable movements during seizures. Using optogenetics, I have identified a cerebellar receiving region of the thalamus, the ventral posteromedial nucleus (VPM), as a powerful region of seizure initiation. The VPM is a major point of convergence of cerebellar and basal ganglia circuitry and could therefore mediate involuntary movements in several diseases. Delivery of light pulses to the VPM in channelrhodopsin-expressing mice elicits immediate, reproducible seizures that begin with myoclonic forelimb movements that progress to severe full body convulsions. I tested the specificity of the VPM as the main locus driving the behavior by stimulating surrounding thalamic nuclei and did not observe obvious behavioral abnormalities. Furthermore, the duration and severity of these optogenetic induced seizures worsens upon repeated stimulation over days. Interestingly, these behaviors are reminiscent of clinical reports that human seizures worsen and become more frequent following the first outbreak. My data raise the intriguing hypothesis that a discrete pool of neurons in the VPM may be a fulcrum site for seizures, into which the cerebellum provides a powerful stimulatory role that controls seizure severity. To test this hypothesis, I will use mice to determine the features of seizure pathophysiology (Aim1), test how cerebellar circuits interact with the thalamus and other regions to generate seizures (Aim2), and uncover the cellular firing mechanisms that produce seizures (Aim3). The experiments in each aim will include state-of-the-art anatomical and in vivo physiological techniques. The completion of these aims will call for a reevaluation of subcortical structures in seizure genesis, especially since the cerebellum was one of the first targets for deep brain stimulation in the treatment of epilepsy. The availability of new therapeutic brain targets for drug-resistant epilepsy will provide alternate healthcare considerations for reducing the impact of severe seizures and improving the quality of life of affected patients.